Project Summary/Abstract There is a major push to substantially improve the sensitivity of positron emission tomography (PET) with systems comprising increased crystal volume and detectors with fast timing capabilities to better exploit 511 keV photon localization with time-of-flight PET (TOF-PET). For these efforts, there is a vital need for advances in TOF-PET detector technologies that provide excellent coincidence time resolution (CTR) and 511 keV photon detection efficiency at reduced cost. To address this, we propose to leverage novel readout electronics that optimize the single photon response shape and single photon time resolution (SPTR) of silicon photomultipliers (SiPMs) to accurately estimate 511 keV photon time of interaction with the mixed Cherenkov/luminescence (MCL) yield from bismuth germinate (BGO). SPTR does not strongly influence CTR for fast and bright scintillators, such as lutetium orthosilicate scintillators (LSO/LYSO). However, a moderate Cherenkov yield mixed with a weak luminescence response creates a more unique scenario where SPTR and single photon response shape play a major role in achievable CTR. With our electronic readout, <285 ps FWHM CTR is achievable for long and narrow BGO crystal elements suitable for clinical PET detectors. This is equivalent to CTR achieved by state-of-the-art (SoA) commercial PET detectors. The novel signal multiplexing strategies we propose to develop will allow us to maintain SoA CTR performance in large area detector modules at the same or reduced channel density than conventional TOF-PET detector designs. BGO is an extremely economical detector material, with a cost that is 4-to-5 fold lower than the standard LSO/LYSO scintillators used in all modern TOF-PET systems. We will develop TOF-PET detector modules with associated front-end signal processing and digital readout electronics. The technology will be ready for ?plug-and-play? integration into reduced cost clinical TOF-PET systems and those that aim to explore ultra-sensitive PET systems with increased detection volume at reduced cost. The proposed PET detector technologies can have a significant impact on quantitative PET imaging. The image signal-to-noise-ratio enabled by the enormous boost in counts from high sensitivity PET systems can be employed to substantially reduce tracer dose and shorten scan time/increase patient throughput, or to better visualize and quantify smaller lesions/features in the presence of significant background, which are important features that can make PET more practical and lower cost, as well as help to expand its roles in patient management.